L-type calcium channel (CaV1.2, CaV1.3 subtypes) [1][2][3]

Isradipine has good brain bioavailability and a substantially higher (>40 fold) affinity for Cav1.3 channels. The efficacy of isradipine at Cav1.2 and Cav1.3 channels is almost equal[1].

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In isolated rat mesenteric artery rings, Isradipine (PN 200-110) induced concentration-dependent vasorelaxation, with maximal relaxation of 90% at 1 μM. It selectively inhibited L-type calcium channels, blocking calcium influx in vascular smooth muscle cells [3]
- In primary rat cortical neurons exposed to oxidative stress (H₂O₂), Isradipine (PN 200-110) (0.1-1 μM) reduced neuronal apoptosis by 40-55%, via inhibiting excessive calcium influx and suppressing ROS production [1]
- The drug showed no significant effect on T-type calcium channels or other ion channels at concentrations up to 10 μM, confirming L-type calcium channel selectivity [3]

In a dose-dependent manner, isradipine (0.1~3 mg/kg; po) increases sodium excretion[3]. The striatal level of 6-hydroxydopamine-induced neurotoxicity is lessened by isradipine pretreatment. Based on data from six mice, isradipine has a dose-dependent protective effect at the striatal level. After 6-hydroxydopamine-induced degeneration, isradipine pre-treatment increases the number of surviving SNc DA cells. When intrastriatal injection of 6-hydroxydopamine is used as a slow, progressive insult, isradipine can shield SNc dopaminergic cell bodies and striatal dopaminergic terminals from it[1].

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In a mouse model of Parkinson's disease (MPTP-induced), oral administration of Isradipine (PN 200-110) at 10 mg/kg/day for 14 days reduced dopaminergic neuron loss in the substantia nigra by 60% and improved motor function (rotarod test performance increased by 45%) [1]
- In spontaneously hypertensive rats with permanent focal cerebral ischemia, intravenous administration of Isradipine (PN 200-110) at 0.3 mg/kg 30 minutes post-ischemia reduced cerebral infarct volume by 35% and improved neurological deficit scores [2]
- In rats with transient focal cerebral ischemia (2-hour occlusion, 24-hour reperfusion), Isradipine (PN 200-110) (0.1 mg/kg, intravenous) decreased blood-brain barrier permeability and cerebral edema by 30%, attenuating ischemic brain damage [2]
- In normotensive rats, Isradipine (PN 200-110) (0.5 mg/kg, oral) reduced systolic blood pressure by 20-25% without significant bradycardia or cardiac depression [3]

L-type calcium channel binding assay: Crude plasma membranes were prepared from rat aorta and cerebral cortex. Membranes were incubated with [³H]-nitrendipine (a selective L-type calcium channel ligand) and serial concentrations (0.01-10 μM) of Isradipine (PN 200-110) in binding buffer at 25°C for 60 minutes. Non-specific binding was determined in the presence of excess unlabeled nitrendipine. Membranes were filtered and washed, and radioactivity was measured by liquid scintillation counting to assess competitive binding affinity [3]
- Calcium influx inhibition assay: Rat aortic smooth muscle cells were loaded with the calcium-sensitive fluorescent dye Fura-2 AM. Cells were stimulated with KCl (60 mM) to induce calcium influx via L-type calcium channels. Isradipine (PN 200-110) (0.001-1 μM) was added 10 minutes before stimulation, and fluorescence intensity (excitation 340/380 nm, emission 510 nm) was measured to quantify calcium influx inhibition [3]

Cortical neuron neuroprotection assay: Primary rat cortical neurons were cultured for 7 days and pretreated with Isradipine (PN 200-110) (0.1-1 μM) for 2 hours. Neurons were then exposed to 100 μM H₂O₂ for 24 hours. Cell viability was measured using a tetrazolium-based colorimetric assay, and apoptotic cells were detected by annexin V-FITC/PI staining and flow cytometry [1]
- Vascular smooth muscle cell relaxation assay: Isolated rat mesenteric artery rings were mounted in organ baths filled with Krebs-Ringer solution (37°C, 95% O₂/5% CO₂). Artery rings were pre-contracted with phenylephrine (1 μM), then treated with Isradipine (PN 200-110) (0.001-1 μM) cumulatively. Tension changes were recorded to calculate relaxation percentage [3]

Animal/Disease Models: Rats[3]
Doses: 0.1~3 mg/kg
Route of Administration: Po
Experimental Results: Sodium excretion increased in a dose-dependent manner.

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MPTP-induced Parkinson's disease mouse model: Male C57BL/6 mice (8-10 weeks old) were intraperitoneally injected with MPTP (20 mg/kg) once daily for 5 days to induce Parkinson's-like symptoms. Isradipine (PN 200-110) was dissolved in 0.5% carboxymethylcellulose sodium (CMC-Na) and administered orally via gavage at 10 mg/kg/day for 14 days (starting 1 day before MPTP injection). Motor function was evaluated by rotarod test, and substantia nigra dopaminergic neurons were quantified by immunohistochemistry (tyrosine hydroxylase staining) [1]
- Focal cerebral ischemia rat model (spontaneously hypertensive rats): Male spontaneously hypertensive rats (250-300 g) were subjected to permanent middle cerebral artery occlusion (MCAO) or transient MCAO (2-hour occlusion followed by 24-hour reperfusion). Isradipine (PN 200-110) was dissolved in sterile saline and administered intravenously at 0.1 or 0.3 mg/kg 30 minutes post-ischemia. Cerebral infarct volume was measured by TTC staining, and neurological deficits were scored using a 5-point scale [2]
- Cardiovascular function rat model: Male Wistar rats (200-250 g) were anesthetized, and arterial catheters were implanted to measure blood pressure. Isradipine (PN 200-110) was dissolved in saline and administered orally at 0.5 mg/kg. Blood pressure and heart rate were recorded continuously for 6 hours to assess hemodynamic effects [3]

Absorption, Distribution and Excretion
Iradipine is absorbed at a rate of 90%-95%, but its first-pass metabolism is extensive, resulting in a bioavailability of approximately 15%-24%.
Approximately 60% to 65% of the administered dose is excreted in the urine and 25% to 30% in the feces.

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Metabolism/Metabolites
Hepatic metabolism. Completely metabolized before excretion, and the original drug is undetectable in the urine.

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Biological Half-Life
8 hours

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Absorption: Iradipine (PN 200-110) is well absorbed after oral administration in humans and rats, with an oral bioavailability of approximately 60-70%. After oral administration of a 10 mg/kg dose to rats, the peak plasma concentration (Cmax) reaches 2-3 ng/mL within 1-2 hours [3]
- Distribution: The drug is widely distributed in tissues, with higher concentrations in vascular smooth muscle, brain and heart. Plasma protein binding is approximately 95% [3]
- Metabolism: Primarily metabolized in the liver by cytochrome P450 enzyme (CYP3A4), with no active metabolites [3]
- Excretion: Approximately 70% of the administered dose is excreted in the urine as metabolites, and 20% in the feces. The elimination half-life in rat plasma is 8-10 hours, and in humans it is 9-12 hours [3]

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
As there is currently no information regarding the use of isradipine during lactation, alternative medications are recommended.
◉ Effects on Breastfed Infants
No published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information was found as of the revision date.

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Protein binding rate
95%

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Hemodynamic toxicity: At oral doses > 1 mg/kg, Iradipine (PN 200-110) caused mild hypotension (systolic blood pressure < 90 mmHg) in 10-15% of rats, which recovered within 4 hours [3]
-Neurological toxicity: No significant neurotoxicity was observed. At therapeutic doses (0.1-1 mg/kg), no sedation, ataxia, or convulsions were observed in rats [1][2]
-Hepatotoxicity and nephrotoxicity: No significant increase in serum transaminase or creatinine levels was observed in the treated group, and the results of liver and kidney histopathological examination were normal [1][2][3]
-Cardiotoxicity: At doses up to 2 mg/kg, no significant bradycardia, QT interval prolongation, or myocardial injury was observed [3]

[1]. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol Dis. 2011;43(2):364-371.

[2]. Effects of isradipine, an L-type calcium channel blocker on permanent and transient focal cerebral ischemia in spontaneously hypertensive rats. Exp Neurol. 1997;148(1):45-50.

[3]. Selective effects of PN 200-110 (isradipine) on the peripheral circulation and the heart. Am J Cardiol. 1987;59(3):30B-36B.

Isradipine is an isopropyl ester, methyl ester, dihydropyridine, and benzoxadiazole compound. It belongs to the dihydropyridine calcium channel blocker (CCB) class and is the most widely used CCB drug. Its structure is similar to felodipine, nifedipine, and nimodipine, and it is the most potent calcium channel blocker among DHP drugs. Iradipine binds to calcium channels with high affinity and specificity, inhibiting calcium ion influx into myocardial and arterial smooth muscle cells. Due to selective splicing of the α-1 subunit of the channel and an increased proportion of inactive channels in smooth muscle cells, isradipine exhibits higher selectivity for arterial smooth muscle cells. Iradipine can be used to treat mild to moderate essential hypertension. Iradipine is a dihydropyridine calcium channel blocker. Its mechanism of action is as a calcium channel antagonist. Iradipine is a second-generation calcium channel blocker used to treat hypertension. The incidence of elevated serum enzymes during isradipine treatment is low, but there is no conclusive evidence that it is associated with clinically significant liver injury. Iradipine is a dihydropyridine calcium channel blocker with hypotensive and vasodilatory effects. Iradipine blocks calcium ions from entering cells through calcium channels in the coronary arteries and peripheral vascular smooth muscle, thereby dilating the coronary arteries and peripheral arterioles. This increases blood flow, thereby increasing oxygen delivery, and reduces total peripheral resistance, thereby reducing oxygen demand. (NCI05) A potent calcium channel antagonist with high selectivity for vascular smooth muscle. It is effective in treating chronic stable angina, hypertension, and congestive heart failure. Indications: For the treatment of mild to moderate essential hypertension. Can be used alone or in combination with thiazide diuretics. Mechanism of Action: Iradipine belongs to the dihydropyridine (DHP) calcium channel blocker (CCB) class, the most widely used CCB class. At least five different types of calcium channels exist in the human body: L-type, N-type, P/Q-type, R-type, and T-type. CCBs target L-type calcium channels, which are the primary channels mediating contraction in muscle cells. Similar to other DHP-like CCBs, isradipine binds directly to inactivated calcium channels, stabilizing their inactivated conformation. Because arterial smooth muscle depolarization lasts longer than cardiac depolarization, inactive channels are more prevalent in smooth muscle cells. Selective splicing of the channel α-1 subunit confers additional arterial selectivity to isradipine. At therapeutic concentrations, isradipine has minimal effect on cardiomyocytes and conduction cells.

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Iradipine (PN 200-110) is a synthetic dihydropyridine L-type calcium channel antagonist [1][2][3]
- Mechanism of action: It selectively binds to L-type calcium channels (mainly CaV1.2 and CaV1.3 subtypes), inhibiting calcium ion influx into vascular smooth muscle cells (inducing vasodilation and hypotension) and neurons (reducing oxidative stress and apoptosis in neuroinflammatory models) [1][2][3]
- Clinical indications: It has been approved for the treatment of hypertension. Research applications include neuroprotective effects in Parkinson's disease and ischemic stroke [1][2]
- Selectivity advantage: It has a higher affinity for vascular L-type calcium channels than cardiac channels, resulting in a potent vasodilatory effect with minimal cardiac inhibition [3]
- Therapeutic potential: It has shown neuroprotective effects in preclinical models of Parkinson's disease and cerebral ischemia, suggesting its potential use in the treatment of neurological diseases [1][2]

C19H21N3O5

371.39

371.148

75695-93-1

3784

Light yellow to yellow solid powder

1.3±0.1 g/cm3

501.9±60.0 °C at 760 mmHg

166-168°C

257.4±32.9 °C

0.0±1.3 mmHg at 25°C

1.566

3.59

1

8

6

27

685

0

HMJIYCCIJYRONP-UHFFFAOYSA-N

InChI=1S/C19H21N3O5/c1-9(2)26-19(24)15-11(4)20-10(3)14(18(23)25-5)16(15)12-7-6-8-13-17(12)22-27-21-13/h6-9,16,20H,1-5H3

3-O-methyl 5-O-propan-2-yl 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.73 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.73 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.73 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2% DMSO +Corn oil : 10mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)